Chronic Kidney Disease-mineral Bone Disorder Research Articles

Utility of Blood Biomarkers to Predict Marrow Iron Stores in Children.

Iron deficiency is common in children with kidney failure, but current guidelines are based on biomarkers of iron stores that may be influenced by inflammation. This is the first study that examined which serum iron indices were associated with stainable marrow iron stores (the gold standard) in this population with kidney failure who underwent bone biopsies. This cross-sectional study enrolled 71 clinically stable children and young adults receiving dialysis who underwent bone biopsy for chronic kidney disease-mineral bone disorder between 2007 through 2011. Bone biopsies were stained with Perls' Prussian blue and independently interpreted by a pathologist blinded to participants' iron parameters and clinical status. Marrow staining was scored absent vs. present to facilitate receiver operator curve (ROC) analysis. In ROC analysis, the ability of serum ferritin to detect stainable marrow iron stores was compared with that of transferrin saturation (TSAT), serum hepcidin, and clinical guideline-based iron deficiency cut-offs for serum iron, TSAT, and their combinations. Mean age was 17.2 ± 4.4 years (range 2-28), and 30% of patients were female. Median dialysis vintage was 1.2 (IQR 0.7, 2.0) years, and 56% were supported by peritoneal dialysis. Mean hemoglobin was 12.4 ± 1.7 g/dl, and 35% were receiving iron supplementation at the time of biopsy. Based on the gold standard of depleted marrow iron stores, 46.5% of patients were iron-deficient. As an indicator of marrow iron staining, serum ferritin provided a higher area under the ROC curve than serum hepcidin, TSAT, or clinical guidelines-based evaluation of TSAT + ferritin. In this cohort of children and young adults with kidney failure, serum ferritin provided the best indication of stainable marrow iron stores, followed by transferrin saturation.

Skeletal parathyroid hormone hyporesponsiveness: a neglected, but clinically relevant reality in chronic kidney disease.

Defining the optimal parathyroid hormone (PTH) target in chronic kidney disease (CKD) is challenging, especially for bone outcomes, due to the substantial variability in the skeleton's response to PTH. Although PTH hyporesponsiveness is as integral a component of CKD-mineral bone disorder as elevated PTH levels, clinical awareness of this condition is limited. In this review, we will discuss factors and mechanisms contributing to PTH hyporesponsiveness in CKD. This knowledge may provide clues towards a personalized approach to treating secondary hyperparathyroidism in CKD. Indicates a link between disturbed phosphate metabolism and impaired skeletal calcium sensing receptor signaling as an important mediator of PTH hyporesponsiveness in CKD. Further, cohort studies with diverse populations point towards differences in mineral metabolism control, rather than genetic or environmental factors, as drivers of the variability of PTH responsiveness. Skeletal PTH hyporesponsiveness in CKD has a multifactorial origin, shows important interindividual variability, and is challenging to estimate in clinical practice. The variability in skeletal responsiveness compromises PTH as a biomarker of bone turnover, especially when considering populations that are heterogeneous in ethnicity, demography, kidney function, primary kidney disease and mineral metabolism control, and in patients treated with bone targeting drugs.

Challenges and Outcomes of Chronic Dialysis in Children: A Narrative Review

Chronic dialysis is a life-saving treatment for children with end-stage renal disease (ESRD). However, it comes with difficult challenges, cardiovascular ones being the most significant and fatal. Chronic kidney disease-mineral bone disorder (CKD-MBD) is also a common complication of chronic dialysis, as it has significant effects on growth and cardiovascular health. Infections are also a significant problem for those on chronic dialysis. The cost of dialysis and the lifestyle of Children with CKD are also not optimal, as they have a significantly lower Health-related quality of life (HRQoL) than children with other chronic illnesses. Children on chronic dialysis face several difficult challenges, which differ between peritoneal dialysis (PD) and hemodialysis (HD). Most of these challenges are manageable or preventable. This review article will discuss some of the challenges that children and their families encounter during chronic dialysis strategies to manage these challenges and the outcomes of long-term kidney dialysis.

Prevalence and Influence of Gout in Patients with Advanced Chronic Kidney Disease: Findings of a Large Retrospective Chart Review

Gout patients have higher mortality, heavier comorbidity burden, and lower quality of life than non-gout patients, but information is sparse on how gout affects advanced CKD patients. This study examined the prevalence and potential health impacts in stage 3–5 CKD patients. Gout was defined as being listed as a comorbidity, ULT use, and/or reported gout symptoms (tophi, >1 flare). Uncontrolled gout was defined as hyperuricemia (serum urate >6 mg/dL) with tophi, ≥2 gout flares/year, or ≥1 swollen/tender joint. This study included 746 patients (55% men, age: 56.2 ± 18.3 years, CKD-duration: 4.0 ± 4.8 years, eGFR: 32.2 ± 15.5 mL/min/1.73 m2), of which 23% met the gout criteria. Prevalence was highest in patients with stage 3b and 4 CKD. Gout patients had a significantly higher prevalence of cardiovascular comorbidities, CKD-mineral bone disorder, and back pain than non-gout patients. Uncontrolled gout patients had more hypertension, joint issues, chronic pain, febuxostat use, and colchicine use than controlled patients. Compared to those without gout, gout patients had higher rates of cardiovascular and bone diseases, with uncontrolled patients having an even higher burden. In conclusion, these data suggest that identifying and monitoring gout in CKD patients provides health benefits. However, more than one-third of gout patients did not have a formal gout diagnosis in their medical record.

International variations in serum PTH and calcium levels and their mortality associations in peritoneal dialysis patients: Results from PDOPPS.

Mineral bone disorder (MBD) in chronic kidney disease (CKD) is associated with high symptom burden, fractures, vascular calcification, cardiovascular disease and increased morbidity and mortality. CKD-MBD studies have been limited in peritoneal dialysis (PD) patients. Here, we describe calcium and parathyroid hormone (PTH) control, related treatments and mortality associations in PD patients. We used data from eight countries (Australia and New Zealand (A/NZ), Canada, Japan, Thailand, South Korea, United Kingdom, United States (US)) participating in the prospective cohort Peritoneal Dialysis Outcomes and Practice Patterns Study (2014-2022) among patients receiving PD for >3 months. We analysed the association of baseline PTH and albumin-adjusted calcium (calciumAlb) with all-cause mortality using Cox regression, adjusted for potential confounders, including serum phosphorus and alkaline phosphatase. Mean age ranged from 54.6 years in South Korea to 63.5 years in Japan. PTH and serum calciumAlb were measured at baseline in 12,642 and 14,244 patients, respectively. Median PTH ranged from 161 (Japan) to 363 pg/mL (US); mean calciumAlb ranged from 9.1 (South Korea, US) to 9.8 mg/dL (A/NZ). The PTH/mortality relationship was U-shaped, with the lowest risk at PTH 300-599 pg/mL. Mortality was nearly 20% higher at serum calciumAlb 9.6+ mg/dL versus 8.4-<9.6 mg/dL. MBD therapy prescriptions varied substantially across countries. A large proportion of PD patients in this multi-national study have calcium and/or PTH levels in ranges associated with substantially higher mortality. These observations point to the need to substantially improve MBD management in PD to optimise patient outcomes. Chronic kidney disease-mineral bone disorder (MBD) is a systemic condition, common in dialysis patients, that results in abnormalities in parathyroid hormone (PTH), calcium, phosphorus and vitamin D metabolism. A large proportion of peritoneal dialysis (PD) patients in this current multi-national study had calcium and/or PTH levels in ranges associated with substantially higher risks of death. Our observational study design limits our ability to determine whether these abnormal calcium and PTH levels cause more death due to possible confounding that was not accounted for in our analysis. However, our findings, along with other recent work showing 48-75% higher risk of death for the one-third of PD patients having high phosphorus levels (>5.5 mg/dL), should raise strong concerns for a greater focus on improving MBD management in PD patients.

Effect of Denosumab on Bone Health, Vascular Calcification, and Health-Related Quality of Life in Hemodialysis Patients with Osteoporosis: A Prospective Observational Study.

Background: Osteoporosis is common in hemodialysis (HD) patients, contributing to cardiovascular risks. Limited research exists on denosumab's efficacy in this group. Our study explores denosumab's effects on bone turnover markers (BTMs) and vascular calcification in chronic kidney disease-mineral bone disorder (CKD-MBD) patients. Methods: In a prospective single-center study, we investigated the effects of denosumab over 2 years on 30 HD patients from a cohort of 185. Annual assessments of bone mineral density (BMD), vascular calcification, and health-related quality of life (HRQL) were conducted and compared with an untreated group. Mineral and bone parameters were analyzed at specific intervals in the treatment group. Results: Denosumab notably raised femoral BMD in the initial year. Most bone turnover markers (BTMs) decreased, except for osteocalcin. Changes in T50 correlated with BTMs. Pre-denosumab supplementation of calcium and vitamin D helped manage mineral imbalances. Post denosumab, parathyroid hormone (PTH) levels increased initially, stabilizing after 3 months. No significant changes occurred in vascular calcification or HRQL. Conclusions: Denosumab exhibited varying effects on BMD improvement, with a stronger impact in the first year that diminished in the second year. Early PTH monitoring was crucial, and extending the administrative period may enhance BMD outcomes compared to the general population.

Soluble Klotho, a Potential Biomarker of Chronic Kidney Disease-Mineral Bone Disorders Involved in Healthy Ageing: Lights and Shadows.

Shortly after the discovery of Klotho, interest grew in its potential role in chronic kidney disease (CKD). There are three isoforms of the Klotho protein: αKlotho, βKlotho and γKlotho. This review will focus on αKlotho due to its relevance as a biomarker in CKD. αKlotho is synthesized mainly in the kidneys, but it can be released into the bloodstream and urine as soluble Klotho (sKlotho), which undertakes systemic actions, independently or in combination with FGF23. It is usually accepted that sKlotho levels are reduced early in CKD and that lower levels of sKlotho might be associated with the main chronic kidney disease-mineral bone disorders (CKD-MBDs): cardiovascular and bone disease. However, as results are inconsistent, the applicability of sKlotho as a CKD-MBD biomarker is still a matter of controversy. Much of the inconsistency can be explained due to low sample numbers, the low quality of clinical studies, the lack of standardized assays to assess sKlotho and a lack of consensus on sample processing, especially in urine. In recent decades, because of our longer life expectancies, the prevalence of accelerated-ageing diseases, such as CKD, has increased. Exercise, social interaction and caloric restriction are considered key factors for healthy ageing. While exercise and social interaction seem to be related to higher serum sKlotho levels, it is not clear whether serum sKlotho might be influenced by caloric restriction. This review focuses on the possible role of sKlotho as a biomarker in CKD-MBD, highlighting the difference between solid knowledge and areas requiring further research, including the role of sKlotho in healthy ageing.

Standardization of PTH measurement by LC-MS/MS: a promising solution for interassay variability

Parathyroid hormone measurement is critical in managing chronic kidney disease-mineral bone disorders. However, there are several commercially available immunoassays with interassay variability. To address this, Cavalier etal. developed standardization of parathyroid hormone measurement by establishing regression equations of each assay against the liquid chromatography coupled to tandem mass spectrometry method. The recalibration successfully reduced interassay variability, allowing for more consistent interpretation. The proposed approach may pave the way for accurate interpretation of parathyroid hormone in clinical practice.

The Dietary Fiber Inulin Slows Progression of Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) in a Rat Model of CKD.

Chronic kidney disease (CKD)-mineral bone disorder (CKD-MBD) leads to fractures and cardiovascular disease. Observational studies suggest beneficial effects of dietary fiber on both bone and cardiovascular outcomes, but the effect of fiber on CKD-MBD is unknown. To determine the effect of fiber on CKD-MBD, we fed the Cy/+ rat with progressive CKD a casein-based diet of 0.7% phosphate with 10% inulin (fermentable fiber) or cellulose (non-fermentable fiber) from 22 weeks to either 30 or 32 weeks of age (~30% and ~15% of normal kidney function; CKD 4 and 5). We assessed CKD-MBD end points of biochemistry, bone quantity and quality, cardiovascular health, and cecal microbiota and serum gut-derived uremic toxins. Results were analyzed by two-way analysis of variance (ANOVA) to evaluate the main effects of CKD stage and inulin, and their interaction. The results showed that in CKD animals, inulin did not alter kidney function but reduced the increase from stage 4 to 5 in serum levels of phosphate and parathyroid hormone, but not fibroblast growth factor-23 (FGF23). Bone turnover and cortical bone parameters were similarly improved but mechanical properties were not altered. Inulin slowed progression of aorta and cardiac calcification, left ventricular mass index, and fibrosis. To understand the mechanism, we assessed intestinal microbiota and found changes in alpha and beta diversity and significant changes in several taxa with inulin, together with a reduction in circulating gut derived uremic toxins such as indoxyl sulfate and short-chain fatty acids. In conclusion, the addition of the fermentable fiber inulin to the diet of CKD rats led to a slowed progression of CKD-MBD without affecting kidney function, likely mediated by changes in the gut microbiota composition and lowered gut-derived uremic toxins. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Real-world usage of Chronic Kidney Disease - Mineral Bone Disorder (CKD-MBD) biomarkers in nephrology practices.

Chronic kidney disease mineral bone disorder (CKD-MBD) is a condition characterized by alterations of calcium, phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23) metabolism that in turn promote bone disorders, vascular calcifications, and increase cardiovascular (CV) risk. Nephrologists' awareness of diagnostic, prognostic, and therapeutic tools to manage CKD-MBD plays a primary role in adequately preventing and managing this condition in clinical practice. A national survey (composed of 15 closed questions) was launched to inquire about the use of bone biomarkers in the management of CKD-MBD patients by nephrologists and to gain knowledge about the implementation of guideline recommendations in clinical practice. One hundred and six Italian nephrologists participated in the survey for an overall response rate of about 10%. Nephrologists indicated that the laboratories of their hospitals were able to satisfy request of ionized calcium levels, 105 (99.1%) of both PTH and alkaline phosphatase (ALP), 100 (94.3%) of 25(OH)D, and 61 (57.5%) of 1.25(OH)2D; while most laboratories did not support the requests of biomarkers such as FGF-23 (intact: 88.7% and c-terminal: 93.4%), Klotho (95.3%; soluble form: 97.2%), tartrate-resistant acid phosphatase 5b (TRAP-5b) (92.5%), C-terminal telopeptide (CTX) (71.7%), and pro-collagen type 1 N-terminal pro-peptide (P1NP) (88.7%). As interesting data regarding Italian nephrologists' behavior to start treatment of secondary hyperparathyroidism (sHPT), the majority of clinicians used KDOQI guidelines (n=55, 51.9%). In contrast, only 40 nephrologists (37.7%) relied on KDIGO guidelines, which recommended referring to values of PTH between two and nine times the upper limit of the normal range. Results point out a marked heterogeneity in the management of CKD-MBD by clinicians as well as a suboptimal implementation of guidelines in Italian clinical practice.

Serum Ferritin Reflects Bone Marrow Iron Stores in Children with End Stage Kidney Disease

Background: Iron deficiency is common in children with end-stage kidney disease (ESKD) but diagnosing iron deficiency in ESKD is challenging as serum indicators of iron stores may be influenced by inflammation and other factors. We examined which of the clinically used serum iron indices were predictive of bone marrow iron stores (the gold standard) in dialysis-dependent children and young adults with ESKD, in the setting of increased nutritional requirements and co-existing inflammation. Methods: This cross-sectional study enrolled 71 clinically-stable children and young adults (age range 2 to 28 years) receiving dialysis, who underwent bone biopsy for CKD-mineral bone disorders between 2007 through 2011. Congenital anomalies of the kidney and urinary tract (CAKUT) and hereditary diseases (63.3%) were the main causes of renal failure, followed by primary glomerulonephritis (36.7%). Bone samples were stained with Perls' Prussian blue and independently interpreted by a pathologist unaware of the patients' iron parameters and clinical status. Staining was scored absent vs present for receiver operator curve (ROC) analysis. In ROC analysis, the ability of serum ferritin to predict bone sample iron stores was compared with serum hepcidin, transferrin saturation (TSAT), and clinical guideline-based iron deficiency cut-offs for serum iron, TSAT, and their combination. We generated optimal cut off points using the Youden's J statistic. Results: Mean age was 17.2 ± 4.4 years, and 30% of subjects were female. Median dialysis vintage was 1.2 (IQR 0.7, 2.0) years, and 56% were supported by peritoneal dialysis. Mean hemoglobin was 12.4 ± 1.7 g/dl, and 35% were receiving iron supplementation at the time of biopsy. Based on gold standard of depleted bone iron stores, 46.5% patients were iron-deficient. As a predictor of bone marrow iron staining, serum ferritin provided the highest area under the ROC curve compared to other tests (Table), but at the usual clinical ferritin cutoff (100 ng/ml) only 22% of true iron-deficient subjects were diagnosed compared to 52% of true iron-deficient subjects using a higher optimal cutoff point for ferritin (188 ng/ml). Conclusions: In children with ESKD, iron deficiency as determined by the gold standard bone iron staining was highly prevalent (close to 50%), and serum ferritin provided the best prediction of bone sample iron stores. Optimal ferritin cutoff for decision-making about iron administration should reflect the current relative risks and benefits of iron therapy. Future trials testing higher ferritin cut-offs and patient centered outcomes in children with ESKD are timely.

Osteoporosis in Renal Disease.

Osteoporosis is a disorder characterized by decreased bone mass and skeletal fragility with increased fracture risk. Chronic kidney disease presents with wide range of bone metabolic disorders, including osteoporosis. Osteoporosis prevalence is high in early stages of CKD; whereas in late stages, it coexists with renal osteodystrophy. Risk factors for osteoporosis include advancing age, low bone mineral density (BMD), glucocorticoid therapy, smoking, alcohol intake, etc. The diagnosis of osteoporosis in renal disease is made after assessment of BMD, in addition to exclusion of chronic kidney disease-mineral bone disorder (CKD-MBD), eliciting history of prior fragility fractures and relevant laboratory investigations. The treatment of osteoporosis varies with the different stages of CKD, with management in stages 1-3 being similar to the general population. Special emphasis must be laid on prevention of fractures as well.

Improving Treatment of CKD-Mineral Bone Disorder (CKD-MBD) Through the Incorporation of Agatston Scores

Improving Treatment of CKD-Mineral Bone Disorder (CKD-MBD) Through the Incorporation of Agatston Scores

Regular laboratory testing and patient survival among patients undergoing maintenance hemodialysis: a Korean nationwide cohort study

Routine laboratory tests are regularly performed in patients undergoing maintenance hemodialysis (HD) to detect anemia, chronic kidney disease-mineral bone disorders, and cardiovascular disease. More frequent laboratory tests may be associated with better outcomes. However, there is little evidence supporting a specific monitoring interval. This study evaluated the impact of regular laboratory testing on mortality in Korean patients undergoing maintenance HD. We used HD quality assessments, and National Health Insurance Service claims data from October to December 2015. In HD quality assessment, 22 tests are recommended every 1–6 months. A total of 34,950 patients were divided into two groups based on the regularity of laboratory testing. A Cox proportional hazards model was used to assess the effects of regular laboratory tests on patient mortality during a mean follow-up duration of 53.7 months. The proportion of patients with and without regular laboratory testing was 85.6% (n = 29,914) and 14.4% (n = 5036), respectively. Patients who underwent regular laboratory testing had a longer dialysis duration, lower serum phosphorus levels and diastolic blood pressure, and higher hemoglobin and single-pool Kt/V levels than those who did not. After adjusting for demographic and clinical parameters, regular laboratory testing independently reduced mortality risk (hazard ratio, 0.90; 95% confidence interval 0.85–0.95; P < 0.001). Regular laboratory testing was associated with a decreased mortality risk among patients undergoing HD. Management of end-stage kidney disease-related complications based on laboratory tests can improve survival.

Vitamin K Status of Patients Undergoing Hemodialysis: Insights from a Cross-Sectional Study

(1) Background: Vitamin K deficiency is a common feature of chronic kidney disease (CKD), leading to impaired bone quality and an increased risk of vascular calcifications. A method to indirectly assess the vitamin K status is measuring the blood level of vitamin K-dependent proteins (VKDP): osteocalcin (OC) and matrix GLA protein (MGP). The aim of this study is to correlate the level of total OC and inactive MGP (dp-uc MGP) with markers of CKD mineral bone disorder (CKD-MBD). (2) Methods: We conducted a single-center cross-sectional study that included 45 CKD G5D patients and measured their blood biochemistry, complete blood count and total osteocalcin and dp-uc MGP contents. (3) Results: We found a strong, statistically significant correlation of the total OC with the markers of CKD-MBD, such as: iPTH, serum calcium and serum phosphorus, and a strong, indirect statistically significant correlation with abdominal circumference. There was also a statistically significant correlation of dp-uc MGP with the markers of inflammation (CRP). Higher levels of dp-uc MGP were found in the patients treated with vitamin K antagonists, non-calcium-based phosphate binders and the vitamin D receptor activator, paricalcitol. (4) Conclusions: In our study, we found that when it is measured indirectly using VKDP levels, vitamin K deficiency is associated with CKD-MBD. Certain widely used medications such as phosphate binders reduce vitamin K absorption, supplementary vitamin D increases vitamin K requirements, and also vitamin K antagonists influence the blood level of VKDPs.

Associations between anemia and FGF23 in the CKiD study

BackgroundFibroblast growth factor 23 (FGF23) is a bone-derived hormone that plays a central role in chronic kidney disease-mineral bone disorder and is associated with CKD progression and cardiovascular morbidity. Factors related to CKD-associated anemia, including iron deficiency, can increase FGF23 production. This study aimed to assess whether anemia and/or iron deficiency are associated with increased circulating concentrations of FGF23 in the large, well-characterized Chronic Kidney Disease in Children (CKiD) study cohort.MethodsHemoglobin concentrations, iron parameters, C-terminal (total) FGF23, intact FGF23, and relevant covariables were measured in cross-sectional analysis of CKiD study subjects.ResultsIn 493 pediatric patients with CKD (median [interquartile range] age 13 [9, 16] years), the median estimated glomerular filtration rate was 48 [35, 61] ml/min/1.73 m2, and 103 patients (21%) were anemic. Anemic subjects had higher total FGF23 concentrations than non-anemic subjects (204 [124, 390] vs. 109 [77, 168] RU/ml, p < 0.001). In multivariable linear regression modeling, anemia was independently associated with higher total FGF23, after adjustment for demographic, kidney-related, mineral metabolism, and inflammatory covariables (standardized β (95% confidence interval) 0.10 (0.04, 0.17), p = 0.002). In the subset of subjects with available iron parameters (n = 191), iron deficiency was not associated with significantly higher total FGF23 concentrations. In the subgroup that had measurements of both total and intact FGF23 (n = 185), in fully adjusted models, anemia was significantly associated with higher total FGF23 (standardized β (95% CI) 0.16 (0.04, 0.27), p = 0.008) but not intact FGF23 (standardized β (95% CI) 0.02 (−0.12, 0.15), p = 0.81).ConclusionsIn this cohort of pediatric patients with CKD, anemia was associated with increased total FGF23 levels but was not independently associated with elevated intact FGF23, suggesting possible effects on both FGF23 production and cleavage. Further studies are warranted to investigate non-mineral factors affecting FGF23 production and metabolism in CKD.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Association between Albuminuria and Serum Phosphate Levels in Non-Dialysis Stage 3-5 Chronic Kidney Disease Patients

Introduction: Chronic kidney disease (CKD) remains a global burden and catastrophic disease as about 697.5 million people suffering from it in 2017. About 42% of CKD mortality in Indonesia is related to cardiovascular complications. Hyperphosphatemia, a manifestation of chronic kidney disease-mineral bone disorder, could increase the risk of cardiovascular mortality. Albuminuria has been proven to inhibit the compensatory mechanisms for hyperphosphatemia, thereby aggravating this condition. This study was conducted to analyze the association between albuminuria and serum phosphate levels among CKD patients in Dr. Soetomo General Academic Hospital, Surabaya, Indonesia.Methods: This cross-sectional study used medical records of 129 non-dialysis stage 3-5 CKD patients at the outpatient clinic of Dr. Soetomo General Academic Hospital from March-November 2021. Descriptive analysis was performed on albuminuria, serum phosphate, age, sex, body mass index, comorbid, blood chemistry tests, and CKD stages data. Correlational analysis was conducted using the Spearman Rank test on albuminuria and serum phosphate levels.Results: The majority of the subjects in this study were male (55.81%); mean age was 55.21±11.99 years; mean BMI was 22.39±2.27 kg/m2; hypertension was found in 65.89% of the patients; mean eGFR was 25.01±16.1 ml/min/1.73 m2 and dominated by CKD stage 3-5. The distribution of albuminuria grade was dominated by heavy albuminuria (&gt;300 mg/g) and the mean serum phosphate level was 4.81±1.9 mg/dl. Spearman Rank analysis found a significant positive correlation with weak association strength (p&lt;0.001; rs=0.277) between albuminuria and serum phosphate levels.Conclusion: There was a significant positive correlation with weak association strength between albuminuria and serum phosphate levels.

#6641 BONE MATERIAL STRENGTH INDEX AND DUAL ENERGY X-RAY ABSORPTIOMETRY IN EVALUATION OF BONE HEALTH IN AUTOSOMAL POLYCYSTIC KIDNEY DISEASE

Abstract Background and Aims Bone material strength measured with the use of impact microindentation technique (OsteoProbe®) has emerged recently as potentially beneficial tool in evaluating bone quality in metabolic bone disorders. Patients with autosomal polycystic kidney disease (ADPKD) carry an increased risk of skeletal complications, both due to deficiency of polycystins and development of chronic kidney disease-mineral bone disorder (CKD-MBD). In our preliminary study, we found that bone material strength index (BMSi) associated with bone mineral density (BMD) measured with the use of dual energy X-ray absorptiometry (DXA) in chronic kidney disese patients (CKD). The aim of the present study was to find if the same applies to patients with ADPKD. We evaluated bone health by measuring BMSi and performing DXA in patients with ADPKD. Method BMSi was measured (OsteoProbe®, Active Life Scientific, USA) in 64 adult patients (37 men, mean age 43 years) with ADPKD in CKD stages G1-4. The measurement of BMSi compared the resistance to impact of microindentation in bone and reference material. After applying local anaesthesia, we impacted the cortical bone in the midshaft tibia in 10 different points. BMD was measured using Hologic Discovery Wi densitometer in multiple sites: lumbar spine, hip, 1/3 distal non-dominant forearm and whole-body. Trabecular bone score (TBS) was calculated using Medimaps TBS iNsight software. Results Mean values of BMSi, TBS and BMD are presented in the Table 1. BMSi in ADPKD patients was lower than average value observed in healthy individuals (85 men and 80 women). A positive linear relationship between BMSi and BMD was found in all of the examined sites with the highest standardized regression coefficient for 1/3 distal forearm (R2 = 0.315, beta = 0.57, p &amp;lt; 0.001) and weakest for lumbar spine (R2 = 0.003, beta = 0.33, p = 0.003). There was no association between BMSi and TBS. Conclusion This is the first report on BMSi in ADPKD patients. In agreement with the notion of a distinct bone phenotype in ADPKD, we observed a median bone material strength index in patients with ADPKD that was lower than the reference value. BMSi associated with BMD, but not with TBS. However, the association with BMD overall is weak, with BMD explaining only 3 to 31% of the variability of BMSi. This observation suggests complementarity and warrants additional studies investigating whether BMSi associates with hard bone endpoints, independent of BMD.

#5653 MEASURABLE IMPROVEMENT IN ABD WITH SMALL CHANGE IN HD SETTING

Abstract Background and Aims Majority of the patients with chronic kidney disease on hemodialysis (CKD HD) have various bone-related pathologies covered under one clinical entity chronic kidney disease – mineral bone disorders (CKD-MBD). One of the most common is the adynamic bone disease (ABD).1 Published data are showing that changes of calcium level in HD fluid might improve the ABD.2,3 Our aim was to assess whether the lowering of the calcium in dialysis fluid will improve the ABD in our HD patients. Method Prospective study was conducted in a single HD centre in a period of 12 months (01.10.2020 until 30.09.2021), with further 6 months follow up. One hundred thirty three HD patients were screened, 64 patients of them had ABD (iPTH &amp;lt;150 ng/ml). 53 patients were enrolled who met the inclusion criteria (age &amp;gt;18 years, and HD vintage &amp;gt;90 days) and 50 completed the study, during which the only phosphate binder used was calcium based. The calcium level content in the dialysis fluid was changed from various calcium content level (1.5 mmol/L; 1.75 mmol/L) and set to 1.25 mmol/L in the enrolled patients. Laboratory parameters were followed each month and the level of iPTH trimonthly. Results Data from 50 patients was collected and analysed, 50.9% (n=27) males. The average age of the cohort was 69.31 years (±12.49), average HD vintage was 51.94 months (±43.82). Average HD time was 254.8 minutes (±14.71) with average blood pump 393.4 ml/min (±44.38). At study end, the iPTH level was significantly changed (p=.00001), from 67.48 ng/ml (±32.85) to 150.38 ng/ml (±92.96). 24 out of 50 patients (48%) had iPTH level &amp;gt;150 ng/ml, p=.00001. Calcium level changed slightly from 2.27 mmol/L (±0.15) to 2.25 mmol/L (±0.18), p=.25. The phosphate level changed from 1.29 mmol/L (±0.49) to 1.55 mmol/L (±0.48), p=.004. The alkaline phosphatase level significantly changed (p=.00002), from 82.61 IU/L (±49.5) to 118.71 IU/L (±50.23). Patients who had iPTH level &amp;gt;150 ng/ml at the study end had level of calcium of 2.2 mmol/L (±0.16), p=.17 compared to patients who had iPTH level &amp;lt;150 ng/ml (level of calcium of 2.31 mmol/L ±0.18; p= .43). There was improvement in the level of phosphate and alkaline phosphatase; 1.31 mmol/L (±0.46) vs. 1.6 mmol/L (±0.46), p=.002 and 82.57 IU/L (±57.22) vs. 130.83 IU/L (±60.24), p= .004, accordingly. Diabetes mellitus (DM) had insignificant impact on ABD in the patient cohort. 66.7% of the patients with DM (n=10) and 40% of the patients without DM (n=14) reached iPTH &amp;gt;150 ng/ml at study end. Intergroup comparison showed significance only in the level of calcium, DM group calcium=2.16 mmol/L (±0.1); non DM group calcium=2.29 mmol/L (±0.1); p=.01. Additionally, at study end, Karnofsky score was higher in patients with iPTH &amp;gt;150 ng/ml, 76.09% (±13.05); p=.009. Patients who did not reach iPTH &amp;gt;150 ng/ml (n=26) were further followed up for 6 months, and 10 of them reached iPTH &amp;gt;150 ng/ml. Conclusion Indirectly minor change in HD setting, as lowering the calcium level in dialysis fluid in a period of more than 12 months, might improve the adynamic bone disease. Presence of diabetes did not showed significant impact on ABD. However, Karnofsky score showed significant improvement, and exercise may also improve ABD in HD patients. These findings might be used as recommendation in low and middle-income countries in which pharmacological treatments for ABD are limited and/or unavailable.

Integrated network pharmacology, transcriptomics, and metabolomics analysis to reveal the mechanism of salt Eucommiae cortex in the treatment of chronic kidney disease mineral bone disorders via the PPARG/AMPK signaling pathway

Ethnopharmacological relevanceThe skeletal complications associated with chronic kidney diseases from stages 3–5 in individuals are called Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD), which increases the incidence of cardiovascular diseases drastically and affects the quality of life of patients seriously. Eucommiae cortex has the effect of tonifying kidneys and strengthening bones, and salt Eucommiae cortex is one of the most commonly used traditional Chinese medicines in the clinical treatment of CKD-MBD instead of Eucommiae cortex. However, its mechanism still remains unexplored. Aim of the studyThe aim of this study was to investigate the effects and mechanisms of salt Eucommiae cortex on CKD-MBD by integrating network pharmacology, transcriptomics, and metabolomics. Materials and methodsThe CKD-MBD mice induced by 5/6 nephrectomy and low calcium/high phosphorus diet were treated with salt Eucommiae cortex. The renal functions and bone injuries were evaluated by serum biochemical detection, histopathological analyses, and femur Micro-CT examinations. Differentially expressed genes (DEGs) between the control group and model group, model group and high-dose Eucommiae cortex group, model group and high-dose salt Eucommiae cortex group were analyzed by transcriptomic analysis. The differentially expressed metabolites (DEMs) between the control group and model group, model group and high-dose Eucommiae cortex group, model group and high-dose salt Eucommiae cortex group were analyzed by metabolomics analysis. The common targets and pathways were obtained by integrating transcriptomics, metabolomics, and network pharmacology, which were identified and verified by in vivo experiments. ResultsThe negative impacts on the renal functions and bone injuries were alleviated with salt Eucommiae cortex treatment effectively. Compared with CKD-MBD model mice, the levels of serum BUN, Ca, and urine Upr were significantly decreased in the salt Eucommiae cortex group. And the Integrated network pharmacology, transcriptomics, and metabolomics analysis revealed that Peroxisome Proliferative Activated Receptor, Gamma (PPARG) was the only common target, mainly involved by AMP-activated Protein Kinase (AMPK) signaling pathways. The activation of PPARG in the kidney tissue was significantly decreased in CKD-MBD mice but increased in the salt Eucommiae cortex treatment. The AMPK signaling pathway was verified and the AMPK expression levels were found to decrease in CKD-MBD mice but increase given salt Eucommiae cortex treatment. ConclusionsOur study presented that salt Eucommiae cortex alleviated the negative impact of CKD-MBD on the renal injury and bone injury of mice induced by 5/6 nephrectomy with the low calcium/high phosphorus diet effectively, which is highly likely achieved through the PPARG/AMPK signaling pathway.